Aggression?acting with the intent to inflict harm?is a universal component of social behavior, and all too often the grim subject of the daily news. One of the most reliable triggers of aggression is frustration, or failing to achieve an expected reward. This state can be adaptive, energizing behaviors to overcome barriers. But it can also lead to anger and violence. In disorders as disparate as PTSD, bipolar disorder, and autism, low frustration tolerance and uncontrolled aggression are among the most prevalent and impairing symptoms in psychiatry. Yet the neurobiology of these behaviors is poorly understood, and current treatment options are grossly inadequate. This proposal aims to define the role of two neuromodulators?dopamine (DA) and serotonin (5HT)?in the neural response to frustrating events. In Aim 1, the candidate will create a mouse model of frustration by combining conditioning tasks with the resident-intruder assay, in which an intruder mouse is added to a resident?s cage to elicit aggression. On test days, the conditioning task will end with an unexpectedly negative outcome, eliciting greater aggression from the resident mouse. In Aim 2, the candidate will use fiber photometry and optogenetics to record and manipulate DA neuron activity and DA release in the nucleus accumbens (NAc) while mice perform the frustration task. DA is a key modulator of motivated behaviors, and has long been considered pro-aggressive. Few studies, however, have recorded DA during frustration or aggression. This experiment will test whether DA release tonically increases with frustration, triggering aggression. In Aim 3, the candidate will use fiber photometry and optogenetics to record and manipulate 5HT neuron activity and 5HT release in the NAc during the frustration task. Unlike DA, 5HT is thought to inhibit behavior, including aggression. But 5HT neurons have not been recorded during aggression. This Aim will test the hypothesis that 5HT release decreases with frustration, and that larger decreases facilitate greater aggression. The proposed studies would be among the first to examine the neural circuit mechanisms of frustration. In the process, the candidate will supplement his background in electrophysiology in head-fixed animals to become proficient in social behaviors and calcium imaging. He will work with an advisory committee comprising world leaders in human (Dr. Emil Coccaro) and rodent (Dr. Klaus Miczek) aggression, frustration (Dr. Ellen Leibenluft), and 5HT (Dr. Liqun Luo), in addition to his primary mentor Dr. Rob Malenka and his career development mentor Dr. Alan Schatzberg. He will take full advantage of the intellectually vibrant environment at Stanford and supplement his technical training with high-quality didactic and professional training via frequent mentor interactions, targeted coursework, and other career and intellectual growth opportunities. By the end of the fellowship, the candidate will be positioned to launch a career as an independent investigator leading a translational research program on the neural basis of aggression and irritability.